Pancreatic cancer intrinsic PI3Kα activity accelerates metastasis and rewires macrophage component.

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micro-metastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We searched for a gene signature that discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. An unbiased approach identified, amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3Kα activation signature as predictive of PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3Kα-selective inhibition prevented macro-metastatic evolution by hindering tumoural cell migratory behaviour independently of genetic alterations. We found that PI3Kα inhibition altered the quantity and the species composition of the produced lipid second messenger PIP3 , with a selective decrease of C36:2 PI-3,4,5-P3 . Tumoural PI3Kα inactivation prevented the accumulation of pro-tumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour cell-intrinsic PI3Kα promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution

Burst activity and heart rhythm modulation in the sympathetic outflow to the heart

In 13 decerebrate, artificially ventilated cats preganglionic sympathetic outflow to the heart was recorded with ECG and ventilation signal. A novel algorithm was implemented that extracts weighted events representing burst occurrences and their size. A multiple threshold strategy was used to separate bursts. Weighted events yielded count signals. Spectral analysis of the count signal revealed a predominance of a discharge synchronous to heart beat at cardiac frequency (CF 453 Hz), a ventilation rhythm at the high frequency (HF 450.3 Hz) of beat-to-beat variability, and in 9 of 13 cats a Mayer's wave lower frequency (LF). The CF component was 3c50% larger in power than both HF and also LF (when present). Spectral analysis at increasing count levels (i.e., with only the events with a weight 65 the considered level) indicated that all rhythms were carried by burst activity and its modulations. A modulation index of HF over CF, MIHF/CF was extracted from dynamic (i.e., ventilation cycle by ventilation cycle) folded histograms of counts. MIHF/CF was significantly higher in the group without LF (0.65\ub10.20, mean\ub1SD, n=4) than in that with LF (0.41\ub10.07, n=9). Burst activity can be a key element in the interactions between cardiovascular variability rhythms

Mass spectrometry-based draft of the mouse proteome.

The laboratory mouse ranks among the most important experimental systems for biomedical research and molecular reference maps of such models are essential informational tools. Here, we present a quantitative draft of the mouse proteome and phosphoproteome constructed from 41 healthy tissues and several lines of analyses exemplify which insights can be gleaned from the data. For instance, tissue- and cell-type resolved profiles provide protein evidence for the expression of 17,000 genes, thousands of isoforms and 50,000 phosphorylation sites in vivo. Proteogenomic comparison of mouse, human and Arabidopsis reveal common and distinct mechanisms of gene expression regulation and, despite many similarities, numerous differentially abundant orthologs that likely serve species-specific functions. We leverage the mouse proteome by integrating phenotypic drug (n > 400) and radiation response data with the proteomes of 66 pancreatic ductal adenocarcinoma (PDAC) cell lines to reveal molecular markers for sensitivity and resistance. This unique atlas complements other molecular resources for the mouse and can be explored online via ProteomicsDB and PACiFIC